Abstract The Chan–Lam reaction is a copper‐mediated or ‐catalyzed formation of a wide variety of carbon–heteroatom bonds from an organoboron compound and a heteroatom nucleophile. In its broadest sense, the reaction allows arylation, vinylation, and alkylation of a wide range of heteroatom‐based functional groups including amines, amides, sulfonamides, N ‐heterocycles, alcohols, phenols, and thiols. The coupling partner is usually a boronic acid, although boronic esters have also been successful. An inexpensive copper mediator or catalyst, such as copper(II) acetate, is employed in the reaction. The typically mild, user‐friendly reaction conditions often involve an atmosphere of air, ambient temperature, and no ligand. This chapter presents a thorough overview of the Chan–Lam reaction with N ‐, O ‐, and S ‐based nucleophiles. The current understanding of the reaction mechanism is discussed along with a detailed overview of the scope and limitations of the process, and representative reaction conditions. Applications in the context of complex molecule synthesis are provided, as are comparisons to complementary metal‐catalyzed heteroatom‐functionalization methods using copper and palladium.
The traditional Nazarov reaction is the conrotatory 4π electrocyclization of conjugated pentadienyl cations, which are derived from Lewis or Brønsted acid activation of 1,4‐pentadien‐3‐ones. This reaction provides an expedient way to assemble carbocyclic products from simple, acyclic starting materials; however, reaction conditions often require at least one equivalent of a strong acid to facilitate cyclization, and the regioselectivity of the standard eliminative termination step is difficult to control. This chapter describes advances in Nazarov methodology since it was last reviewed in Organic Reactions in 1994. The discussion is focused on the preparation and use of alternative substrates to access the requisite pentadienyl cation as well as methods to induce cyclization with new and asymmetric catalytic systems. Also presented is a discussion of the interrupted Nazarov reaction, which utilizes both cationic and enolate intermediates to form new bonds or to initiate cascade or tandem reaction sequences. Both inter‐ and intramolecular interrupted Nazarov reactions generate highly functionalized products, some of which may possess four contiguous stereogenic centers. Trapping events can involve heteronucleophiles, π‐systems, or structural rearrangements, which occur in a stereocontrolled fashion.
Atropisomeric biaryl compounds are prepared by coupling two aryl partners in the presence of a chiral catalyst. When these biaryl products contain three or more substituents adjacent to the new aryl–aryl bond, the barrier to bond rotation becomes sufficiently high to enable the isolation of single enantiomers. This structural feature is found in numerous natural products and chiral ligand frameworks. The asymmetric catalytic construction of a carbon–carbon bond between two sp 2 ‐hybridized aryl fragments can be achieved with redox‐neutral cross‐couplings, reductive homo‐couplings, couplings through C–H activation, oxidative couplings, and couplings by nucleophilic addition to oxidized partners. Although considerable emphasis has been placed on traditional palladium‐catalyzed cross‐coupling reactions, including asymmetric Suzuki coupling, there have been significant advances in both reductive and oxidative approaches. Functional‐group tolerance on the coupling partners is varied and often dependent on the choice of chiral catalyst and ligand. Where appropriate, mechanisms and proposed stereochemical models are used to explain the observed axial chirality. These transformations are showcased in the syntheses of natural products and novel chiral ligands. The goal of this chapter is to demonstrate the significance of catalytic atroposelective aryl–aryl bond‐forming reactions, including the continued development of catalytic systems to achieve excellent yields and enantioselectivities. Additionally, some less‐common approaches towards catalytic atroposelective aryl–aryl bond formation are discussed.
The regioselective C−H functionalization of arenes is an ideal method for preparing substituted aromatic compounds, which are ubiquitous scaffolds in natural products, pharmaceuticals, and advanced materials. Palladium(0)‐catalyzed, norbornene‐mediated C−H functionalization—now known as the Catellani reaction—is a particularly efficient and modular means to access densely substituted aromatic compounds. Inspired by the Catellani reaction, many palladium(II)‐catalyzed variants have been developed, further expanding the synthetic utility of this chemistry. The Catellani reaction functionalizes both the ortho and ipso positions of the starting haloarene. Products are obtained with excellent regioselectivity, and enantioenriched norbornene derivatives may be used to render the reaction enantioselective. This method enables ortho ‐alkylation, ‐arylation, and ‐amination of various arene substrates, and can be combined with other palladium‐catalyzed processes. The mechanism, development, and applications of Catellani‐type reactions are discussed in this chapter.
Conjugated alkynes are valuable intermediates in the synthesis of natural products, agrochemicals, pharmaceuticals, fine chemicals, and organic molecular materials. Since its introduction in 1975, the palladium‐catalyzed Sonogashira reaction has become the primary choice for the construction of sp–sp 2 carbon–carbon bonds in aryl‐, heteroaryl‐, and alkenyl‐substituted alkynes. A vast range of reaction conditions have been explored to expand and optimize the scope of the Sonogashira reaction, including sustainable variants, microwave‐assisted cross couplings, and cross couplings performed in water. Research efforts also target the development of improved catalytic systems for the Sonogashira reaction, such as solid‐supported palladium catalysts and nanoparticles, the use of N ‐heterocyclic carbenes (NHCs) as ligands, as well as copper‐free variants of the reaction. This Chapter reviews the application of the palladium‐catalyzed Sonogashira cross coupling of terminal alkynes with aryl or alkenyl halides and triflates. Coupling reactions that form conjugated alkynes via alternative methods, or use different electrophiles, catalysts, or alkynes, are also briefly described.
